Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
  • C07D213/71—Sulfur atoms to which a second hetero atom is attached
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/38—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• Isocitrate dehydrogenase also known as IDH
• IDH is an enzyme which participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative
• Neoactive mutants can increase the level of neoactive product, while other processes, e.g., in the case of 2HG, e.g., R-2HG, enzymatic degradation of 2HG, e.g., by 2HG dehydrogenase, reduce the level of neoative product. An incorrect balance is associated with disease. Accordingly, there is an ongoing need for modulators of IDH mutants having alpha hydroxyl neoactivity.
• Described herein are compounds, compositions (e.g., pharmaceutical compositions), and methods of treating cancer.
• the compounds and compositions can be used to modulate an isocitrate dehydrogenase (IDH) mutant (e.g., IDHlm or IDH2m) having alpha hydroxyl neoactivity.
• kits comprising a compound or composition of this invention.
• a compound and/or pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:
• W, X, Y and Z are each independently selected from CH or N;
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are independently selected from a bond, oxygen or NR C ;
• A is aryl or heteroaryl each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from alkyl, acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , -C(0)NR c R c' , cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, or heteroaralkyl; each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and -OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms they are attached to form an optionally substituted heterocyclyl;
• each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl; each R b is independently alkyl;
• each R c and R c is independently selected from hydrogen, alkyl, alkyl- C(0)OR b and alkenyl;
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• h 0, 1, 2;
• g 0, 1 or 2.
• included is a method of treating a subject having a cell proliferation-related disorder, e.g., a precancerous disorder, or cancer, the method comprising by administering to the subject a compound or composition described herein (e.g., a compound of formula (I)), for example, a therapeutically effective amount of a compound described herein.
• a compound or composition described herein e.g., a compound of formula (I)
• aciduria e.g., 2-hydroxyglutaric aciduria
• the cell proliferation- related disorder can be characterized by a somatic allele, e.g., a preselected allele, or mutant allele, of an IDH, e.g., IDH1 or IDH2, which encodes a mutant IDH, e.g., IDH1 or IDH2, enzyme having a neoactivity.
• neoactivity refers to alpha hydroxy neoactivity. Neoactivity and alpha hydroxyl neoactivity are used interchanagly herein.
• Alpha hydroxy neoactivity is the ability to convert an alpha ketone to an alpha hydroxy.
• alpha hydroxy neoactivity proceeds with a reductive cofactor, e.g., NADPH or NADH.
• the alpha hydroxy neoactivity is 2HG neoactivity.
• 2HG neoactivity refers to the ability to convert alpha ketoglutarate to 2-hydroxyglutarate (sometimes referred to herein as 2HG), e.g., R-2- hydroxyglutarate (sometimes referred to herein as R-2HG).
• the compound (e.g., a compound of formula (I)) or composition described herein results in lowering the level of a neoactivity product, e.g., 2HG, e.g., R-2HG.
• the compound (e.g., a compound of formula (I)) or composition described herein reduces the level a neoactivity of an IDH, e.g., IDH1 or IDH2, e.g., 2HG neoactivity.
• the compound (e.g., a compound of formula (I)) or composition described herein reduces the level of the product of a mutant having a neoactivity of an IDH, e.g., IDH1 or IDH2 mutant, e.g., it reduces the level of 2HG, e.g., R-2HG.
• the compound described herein inhibits, e.g., specifically, a neoactivity of an IDH, e.g., IDH1 or IDH2, e.g., 2HG neoactivity; or inhibits both the wildtype activity and a neoactivity of an IDH, e.g., IDH1 or IDH2, e.g, 2HG neoactivity.
• the IDH is IDH1 and the neoactivity is 2HG neoactivity.
• Mutations in IDH1 associated with 2HG neoactivity include mutations at residue 132, e.g., R132H or R132C.
• IDH1 mutations associated with alpha hydroxy neoactivity include mutations at residue 71, e.g., a mutation having other than a Val at residue 71, e.g., V71I.
• IDH1 mutations associated with alpha hydroxy neoactivity include mutations at residue 100, e.g., a mutation having other than an Arg at residue 100, and mutations at residue 109, e.g., a mutation having other than an Arg atu residue 109.
• the IDH is IDH2 and the neoactivity of the IDH2 mutant is 2HG neoactivity. Mutations in IDH2 associated with 2HG neoactivity include mutations at residue 172. Mutations in IDH2 associated with 2HG neoactivity include mutations at residue 140.
• Treatment methods described herein can comprise evaluating a neoactivity genotype or phenotype. Methods of obtaining and analyzing samples, and the in vivo analysis in subjects, described elsewhere herein, e.g., in the section entitled, "Methods of evaluating samples and/or subjects," can be combined with this method. In an embodiment, prior to or after treatment, the method includes evaluating the growth, size, weight, invasiveness, stage or other phenotype of the cell proliferation-related disorder.
• the method includes evaluating the IDH, e.g., IDHl or IDH2, neoactivity genotype, e.g., 2HG genotype, or neoactivity phenotype, e.g., 2HG, e.g., R-2HG, phenotype.
• Evaluating the 2HG genotype can comprise determining if an IDHl or IDH2 mutation having neoactivity, e.g., 2HG neoactivity, is present, e.g., a mutation disclosed herein having neoactivity, e.g., 2HG neoactivity.
• Neoactivity phenotype e.g., 2HG, e.g., R-2HG
• phenotype refers to the level of neoactivity product (i.e., alpha hydroxyl neoactivity product), e.g., 2HG, e.g., R-2HG, level of neoactivity, e.g., 2HG neoactivity, or level of mutant IDH enzyme having neoactivity, e.g., 2HG neoactivity (or corresponding mRNA).
• the evaluation can be by a method described herein.
• the subject can be evaluated, before or after treatment, to determine if the cell proliferation-related disorder is characterized by a neoactivity product, e.g., 2HG, e.g., R-2HG.
• a neoactivity product e.g., 2HG, e.g., R-2HG.
• a cancer e.g., a glioma or brain tumor in a subject
• can be analyzed e.g., by imaging and/or spectroscopic analysis, e.g., magnetic resonance- based analysis, e.g., MRI and/or MRS, e.g., before or after treatment, to determine if it is characterized by presence of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• imaging and/or spectroscopic analysis e.g., magnetic resonance- based analysis, e.g., MRI and/or MRS, e.g., before or after treatment
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG.
• the method comprises evaluating, e.g., by direct examination or evaluation of the subject, or a sample from the subject, or receiving such information about the subject, the IDH, e.g., IDHl or IDH2, genotype, or an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG phenotype of, the subject, e.g., of a cell, e.g., a cancer cell, characterized by the cell proliferation-related disorder.
• the IDH e.g., IDHl or IDH2
• genotype e.g., genotype
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG phenotype of
• the subject e.g., of a cell, e.g., a cancer cell, characterized by the cell proliferation-related disorder.
• the evaluation can be, e.g., by DNA sequencing, immuno analysis, evaluation of the presence, distribution or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, e.g., from spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement, sample analysis such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy).
• spectroscopic analysis e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement
• sample analysis such as serum or spinal cord fluid analysis
• surgical material e.g., by mass-spectroscopy
• this information is used to determine or confirm that a proliferation-related disorder, e.g., a cancer, is characterized by an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• this information is used to determine or confirm that a cell proliferation-related disorder, e.g., a cancer, is characterized by an IDH, e.g., IDHl or IDH2, allele described herein, e.g., an IDHl allele having a mutation, e.g., a His or Cys at residue 132, or an IDH2 allele having a mutation at residue 172 or residue 140.
• the subject is evaluated or monitored by a method described herein, e.g., the analysis of the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, e.g., to select, diagnose or prognose the subject, to select an inhibitor, or to evaluate response to the treatment or progression of disease.
• a method described herein e.g., the analysis of the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, e.g., to select, diagnose or prognose the subject, to select an inhibitor, or to evaluate response to the treatment or progression of disease.
• the cell proliferation-related disorder is a tumor of the CNS, e.g., a glioma, a leukemia, e.g., AML or ALL, e.g., B-ALL or T-ALL, prostate cancer, or myelodysplasia or myelodysplastic syndrome and the evaluation is: evaluation of the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG; or evaluation of the presence, distribution, or level of a neoactivity, e.g., 2HG neoactivity, of an IDHl or IDH2, mutant protein.
• a glioma e.g., a leukemia, e.g., AML or ALL, e.g., B-ALL or T-ALL, prostate cancer, or myelodysplasia or myelodysplastic syndrome
• the evaluation is: evaluation of the presence, distribution, or level of an
• the genotype of an IDH mutation associated with alpha hydroxy neoactivity e.g., 2HG neoactivity, other than a mutation at reside 132 of IDHl or other than a mutation at residue 140 or 172 of IDH2, is determined.
• an IDHl mutation at residue 100 or 109 of IDHl associated with alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutation having other than an Arg at residue 100 or 109 is determined, e.g., by sequencing genomic DNA or cDNA, from an affected cell.
• the disorder is other than a solid tumor.
• the disorder is a tumor that, at the time of diagnosis or treatment, does not have a necrotic portion.
• the disorder is a tumor in which at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IHD, e.g., IDHl or IDH2, mutation having 2HG neoactivity, at the time of diagnosis or treatment.
• the cell proliferation-related disorder is a cancer, e.g., a cancer described herein, characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• the tumor is characterized by increased levels of an alpha hydroxy neoactivity product, 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity, product, e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is a tumor of the CNS, e.g., a glioma, e.g., wherein the tumor is characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• Gliomas include astrocytic tumors, oligodendroglial tumors, oligoastrocytic tumors, anaplastic astrocytomas, and glioblastomas.
• the tumor is characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
• the IDHl allele encodes an IDHl having other than an Arg at residue 132.
• the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Yan et al., at residue 132, according to the sequence of SEQ ID NO: l (see also Fig. 1).
• the allele encodes an IDHl having His at residue 132.
• the allele encodes an IDHl having Ser at residue 132.
• the IDHl allele has an A (or any other nucleotide other than C) at nucleotide position 394, or an A (or any other nucleotide other than G) at nucleotide position 395.
• the allele is a C394A or a G395A mutation according to the sequence of SEQ ID NO:2.
• the method comprises selecting a subject having a glioma, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele having His or Cys at residue 132 (SEQ ID NO: l).
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having His or Cys at residue 132 (SEQ ID NO: 1).
• the IDHl allele encodes an IDHl having other than a Val at residue 71, e.g., V71I.
• the method comprises selecting a subject having a glioma, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than an Arg at residue 109.
• the method comprises selecting a subject having a glioma, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity, product, e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is localized or metastatic prostate cancer, e.g., prostate adenocarcinoma, e.g., wherein the cancer is characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• the cancer is characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
• the IDHl allele encodes an IDHl having other than an Arg at residue 132.
• the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Kang et al, 2009, Int. J. Cancer, 125: 353-355 at residue 132, according to the sequence of SEQ ID NO: l (see also FIG. 1).
• the allele encodes an IDHl having His or Cys at residue 132.
• the IDHl allele has a T (or any other nucleotide other than C) at nucleotide position 394, or an A (or any other nucleotide other than G) at nucleotide position 395.
• the allele is a C394T or a G395A mutation according to the sequence of SEQ ID NO:2.
• the method comprises selecting a subject having prostate cancer, e.g., prostate adenocarcinoma, wherein the cancer is characterized by an IDHl allele described herein, e.g., an IDHl allele having His or Cys at residue 132 (SEQ ID NO: l).
• prostate cancer e.g., prostate adenocarcinoma
• the cancer is characterized by an IDHl allele described herein, e.g., an IDHl allele having His or Cys at residue 132 (SEQ ID NO: l).
• the method comprises selecting a subject having prostate cancer, e.g., prostate adenocarcinoma, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having His or Cys at residue 132 (SEQ ID NO:2).
• the IDHl allele encodes an IDHl having other than a Val at residue 71, e.g., V71I.
• the method comprises selecting a subject having prostate cancer, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the method comprises selecting a subject having prostate cancer, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having lie at residue 71 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having prostate cancer, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having prostate cancer, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having prostate cancer, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is a hematological cancer, e.g., a leukemia, e.g., AML, or ALL, wherein the hematological cancer is characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• the cancer is characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
• the cell proliferation-related disorder is acute lymphoblastic leukemia (e.g., an adult or pediatric form), e.g., wherein the acute lymphoblastic leukemia (sometimes referred to herein as ALL) is characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• the ALL can be, e.g., B-ALL or T-ALL.
• the cancer is characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
• the IDHl allele is an IDHl having other than an Arg at residue 132 (SEQ ID NO: l).
• the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Kang et a.l, at residue 132, according to the sequence of SEQ ID NO: l (see also FIG. 1).
• the allele encodes an IDHl having Cys at residue 132.
• the IDHl allele has a T (or any other nucleotide other than C) at nucleotide position 394.
• the allele is a C394T mutation according to the sequence of SEQ ID NO:2.
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, characterized by an IDHl allele described herein, e.g., an IDHl allele having Cys at residue 132 according to the sequence of SEQ ID NO: l.
• the method comprises selecting a subject ALL, e.g., B-ALL or T-ALL, on the basis of cancer being characterized by having an IDHl allele described herein, e.g., an IDHl allele having Cys at residue 132 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than a Val at residue 71, e.g., V71I.
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele having lie at residue 71 (SEQ ID NO: l).
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• ALL e.g., B-ALL or T-ALL
• unwanted i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is acute myelogenous leukemia (e.g., an adult or pediatric form), e.g., wherein the acute myelogenous leukemia (sometimes referred to herein as AML) is characterized by an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• the cancer is characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non- diseased cells of the same type.
• the IDHl allele is an IDHl having other than an Arg at residue 132 (SEQ ID NO: l).
• the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Kang et ah , at residue 132, according to the sequence of SEQ ID NO: l (see also FIG. 1).
• the allele encodes an IDHl having Cys at residue 132.
• the IDHl allele has a T (or any other nucleotide other than C) at nucleotide position 394.
• the allele is a C394T mutation according to the sequence of SEQ ID NO:2.
• the method comprises selecting a subject having acute myelogenous lymphoplastic leukemia (AML) characterized by an IDHl allele described herein, e.g., an IDHl allele having Cys at residue 132 according to the sequence of SEQ ID NO: l.
• AML acute myelogenous lymphoplastic leukemia
• the method comprises selecting a subject having acute myelogenous lymphoplastic leukemia (AML) on the basis of cancer being characterized by having an IDHl allele described herein, e.g., an IDHl allele having Cys at residue 132 (SEQ ID NO: l).
• AML acute myelogenous lymphoplastic leukemia
• the method comprises selecting a subject having acute myelogenous lymphoplastic leukemia (AML), on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• AML acute myelogenous lymphoplastic leukemia
• the IDHl allele encodes an IDHl having other than a Val at residue 71, e.g., V71I.
• the method comprises selecting a subject having AML wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the method comprises selecting a subject having AML, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having AML, wherein the cancer is characterized by having an IDHl allele described herein, e.g., an IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having AML, on the basis of the cancer being characterized by an IDHl allele described herein, e.g., an IDHl allele having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method further comprises evaluating the subject for the presence of a mutation in the NRAS or NPMc gene.
• the cell proliferation-related disorder is myelodysplasia or myelodysplastic syndrome, e.g., wherein the myelodysplasia or myelodysplastic syndrome is characterized by having an IDHl somatic mutant having alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., a mutant described herein.
• the disorder is characterized by increased levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, as compared to non-diseased cells of the same type.
• the IDHl allele is an IDHl having other than an Arg at residue 132 (SEQ ID NO: l).
• the allele encodes His, Ser, Cys, Gly, Val, Pro or Leu, or any residue described in Kang et a.l, according to the sequence of SEQ ID NO: l (see also FIG. 1).
• the allele encodes an IDHl having Cys at residue 132.
• the IDHl allele has a T (or any other nucleotide other than C) at nucleotide position 394.
• the allele is a C394T mutation according to the sequence of SEQ ID NO:2.
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome characterized by an IDHl allele described herein, e.g., an IDHl allele having Cys at residue 132 according to the sequence of SEQ ID NO: l.
• IDHl allele described herein, e.g., an IDHl allele having Cys at residue 132 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than a Val at residue 71, e.g., V71I.
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome wherein the disorder is characterized by having an IDHl allele described herein, e.g., an IDHl allele having lie at residue 71 (SEQ ID NO: l).
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome, on the basis of the disorder being characterized by an IDHl allele described herein, e.g., an IDHl allele having He at residue 71 (SEQ ID NO: l).
• the IDHl allele encodes an IDHl having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome wherein the disorder is characterized by having an IDHl allele described herein, e.g., an IDHl allele other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome on the basis that the disorder is characterized by an IDHl allele described herein, e.g., an IDHl allele having other than an Arg at residue 100 or other than an Arg at residue 109.
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is a glioma, characterized by a mutation, or preselected allele, of IDH2 associated with an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• the IDH2 allele encodes an IDH2 having other than an Arg at residue 172.
• the allele encodes Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et al., at residue 172, according to the sequence of SEQ ID NO:4(see also Fig. 2).
• the allele encodes an IDH2 having Lys at residue 172.
• the allele encodes an IDH2 having Met at residue 172.
• the method comprises selecting a subject having a glioma, wherein the cancer is characterized by having an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having a glioma, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is a prostate cancer, e.g., prostate adenocarcinoma, characterized by a mutation, or preselected allele, of IDH2 associated with an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• the IDH2 allele encodes an IDH2 having other than an Arg at residue 172.
• the allele encodes Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et al., at residue 172, according to the sequence of SEQ ID NO:4(see also Fig. 2).
• the allele encodes an IDH2 having Lys at residue 172.
• the allele encodes an IDH2 having Met at residue 172.
• the method comprises selecting a subject having a prostate cancer, e.g., prostate adenocarcinoma, wherein the cancer is characterized by having an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• a prostate cancer e.g., prostate adenocarcinoma
• the cancer is characterized by having an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having a prostate cancer, e.g., prostate adenocarcinoma, on the basis of the cancer being characterized by an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• a prostate cancer e.g., prostate adenocarcinoma
• an IDH2 allele described herein e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having a prostate cancer, e.g., prostate adenocarcinoma, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• a prostate cancer e.g., prostate adenocarcinoma
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is ALL, e.g., B-ALL or T-ALL, characterized by a mutation, or preselected allele, of IDH2 associated with an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• the IDH2 allele encodes an IDH2 having other than an Arg at residue 172.
• the allele encodes Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et al., at residue 172, according to the sequence of SEQ ID NO:4(see also Fig. 2).
• the allele encodes an IDH2 having Lys at residue 172.
• the allele encodes an IDH2 having Met at residue 172.
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, wherein the cancer is characterized by having an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, on the basis of the cancer being characterized by an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having ALL, e.g., B-ALL or T-ALL, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• ALL e.g., B-ALL or T-ALL
• unwanted i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is AML, characterized by a mutation, or preselected allele, of IDH2 associated with an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• the IDH2 allele encodes an IDH2 having other than an Arg at residue 172.
• the allele encodes Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et al., at residue 172, according to the sequence of SEQ ID NO:4 (see also Fig. 2).
• the allele encodes an IDH2 having Lys at residue 172.
• the allele encodes an IDH2 having Met at residue 172.
• the method comprises selecting a subject having AML, wherein the cancer is characterized by having an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having AML, on the basis of the cancer being characterized by an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having AML, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• the cell proliferation-related disorder is myelodysplasia or myelodysplastic syndrome, characterized by a mutation, or preselected allele, of IDH2.
• the IDH2 allele encodes an IDH2 having other than an Arg at residue 172.
• the allele encodes Lys, Gly, Met, Trp, Thr, Ser, or any residue described in described in Yan et al., at residue 172, according to the sequence of SEQ ID NO:4 (see also Fig. 2).
• the allele encodes an IDH2 having Lys at residue 172.
• the allele encodes an IDH2 having Met at residue 172.
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome,wherein the cancer is characterized by having an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome, on the basis of the cancer being characterized by an IDH2 allele described herein, e.g., an IDH2 allele having Lys or Met at residue 172 (SEQ ID NO:4).
• the method comprises selecting a subject having myelodysplasia or myelodysplastic syndrome, on the basis of the cancer being characterized by unwanted, i.e., increased, levels of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG.
• a product of the neoactivity is 2HG (e.g., R-2HG) which acts as a metabolite.
• a product of the neoactivity is 2HG (e.g., R-2HG) which acts as a toxin, e.g., a carcinogen.
• the methods described herein can result in reduced side effects relative to other known methods of treating cancer.
• an IDH1 mutation include a mutation at residue 70 (e.g., a mutation having other than a Gly at residue 70, (e.g., G70V)), 130 (e.g., a mutation having other than an lie at residue 130 (e.g., I130M)), 133 (e.g., a mutation having other than a His at residue 133 (e.g., H133Q)), 135 (e.g., a mutation having other than a His at residue 133 (e.g., H133Q)), or 178 (e.g., a mutation having a residue other than a Val at residue 178 (e.g., V178I)), where such mutation is associated with alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• a mutation at residue 70 e.g., a mutation having other than a Gly at residue 70, (e.g., G70V)
• 130 e.g., a mutation having other
• the cell proliferation-related disorder is thyroid cancer, fibrosarcoma or melanoma.
• the method comprises providing a second treatment, to the subject, e.g., surgical removal, irradiation or administration of a chemotherapeutitc agent, e.g., an administration of an alkylating agent.
• Administration (or the establishment of therapeutic levels) of the second treatment can: begin prior to the beginning or treatment with (or prior to the establishment of therapeutic levels of) the inhibitor; begin after the beginning or treatment with (or after the establishment of therapeutic levels of) the inhibitor, or can be administered concurrently with the inhibitor, e.g., to achieve therapeiutc levels of both concurrently.
• the cell proliferation-related disorder is a CNS tumor, e.g., a glioma
• the second therapy comprises administration of one or more of: radiation; an alkylating agent, e.g., temozolomide, e.g., Temoader®, or BCNU; or an inhibitor of HER1/EGFR tyrosine kinase, e.g., erlotinib, e.g., Tarceva®.
• the second therapy e.g., in the case of glioma, can comprise implantation of BCNU or carmustine in the brain, e.g., implantation of a Gliadel® wafer.
• the second therapy e.g., in the case of glioma, can comprise administration of imatinib, e.g., Gleevec®.
• the cell proliferation-related disorder is prostate cancer and the second therapy comprises one or more of: androgen ablation; administration of a microtubule stabilizer, e.g., docetaxol, e.g., Taxotere®; or administration of a topoisomerase II inhibitor, e.g., mitoxantrone.
• a microtubule stabilizer e.g., docetaxol, e.g., Taxotere®
• a topoisomerase II inhibitor e.g., mitoxantrone.
• the cell proliferation-related disorder is ALL, e.g., B-ALL or T-ALL
• the second therapy comprises one or more of: induction phase treatment comprising the administration of one or more of: a steroid; an inhibitor of microtubule assembly, e.g., vincristine; an agent that reduces the availability of asparagine, e.g., asparaginase; an anthracycline; or an antimetabolite, e.g., methotrexate, e.g., intrathecal methotrexate, or 6-mercaptopurine;
• induction phase treatment comprising the administration of one or more of: a steroid; an inhibitor of microtubule assembly, e.g., vincristine; an agent that reduces the availability of asparagine, e.g., asparaginase; an anthracycline; or an antimetabolite, e.g., methotrexate, e.g., intrathecal methotre
• consolidation phase treatment comprising the administration of one or more of: a drug listed above for the induction phase; an antimetabolite, e.g., a guanine analog, e.g., 6-thioguanine; an alkylating agent , e.g., cyclophosphamide; an antimetabolite, e.g., AraC or cytarabine; or an inhibitor of topoisomerase I, e.g., etoposide; or
• maintenance phase treatment comprising the administration of one or more of the drugs listed above for induction or consolidation phase treatment.
• the cell proliferation-related disorder is AML and the second therapy comprises administration of one or more of: an inhibitor of topoisomerase II, e.g., daunorubicin, idarubicin, topotecan or mitoxantrone; an inhibitor of topoisomerase I, e.g., etoposide; or an anti-metabolite, e.g., AraC or cytarabine.
• an inhibitor of topoisomerase II e.g., daunorubicin, idarubicin, topotecan or mitoxantrone
• an inhibitor of topoisomerase I e.g., etoposide
• an anti-metabolite e.g., AraC or cytarabine.
• halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
• alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
• Ci- Ci2 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it.
• haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). Alkyl may be optionally substituted.
• arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
• Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
• alkylene refers to a divalent alkyl, e.g., -CH 2 -, -CH 2 CH 2 -, and -
• alkenyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds.
• alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.
• One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
• alkynyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
• One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
• alkylamino and dialkylamino refer to -NH(alkyl) and - NH(alkyl) 2 radicals respectively.
• aralkylamino refers to a -NH(aralkyl) radical.
• alkylaminoalkyl refers to a (alkyl)NH-alkyl- radical; the term dialkylaminoalkyl refers to a (alkyl ⁇ N-alkyl- radical
• alkoxy refers to an - O-alkyl radical.
• mercapto refers to an SH radical.
• thioalkoxy refers to an -S-alkyl radical.
• thioaryloxy refers to an -S-aryl radical.
• aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
• aryl refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., by one or more substituents).
• aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.
• cycloalkyl as employed herein includes saturated cyclic, bicyclic, tricyclic,or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted (e.g., by one or more substituents).
• the cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
• heteroaryl refers to a fully aromatic 5-8 membered monocyclic, 8- 12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms selected independently from N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any ring atom can be substituted (e.g., by one or more substituents). The point of attachment of a heteroaryl is on the ring containing said heteroatom(s).
• heterocyclyl refers to a nonaromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively).
• the point of attachment of a heterocyclyl is on the ring containing said heteroatom(s).
• the heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Any ring atom can be substituted (e.g., by one or more substituents).
• heterocyclyl groups can contain fused rings. Fused rings are rings that share a common carbon atom.
• heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl,
• Bicyclic and tricyclic ring systems containing one or more heteroatoms and both aromatic and non-aromatic rings are considered to be heterocyclyl groups according to the present definition.
• saturated or partially saturated heterocyclyl refers to a non- aromatic cylic structure that includes at least one heteroatom.
• Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
• the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
• substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate,
• heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
• cycloalkenyl refers to partially unsaturated, nonaromatic, cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 5 to 12 carbons, preferably 5 to 8 carbons.
• the unsaturated carbon may optionally be the point of attachment of the cycloalkenyl substituent. Any ring atom can be substituted (e.g., by one or more substituents).
• the cycloalkenyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkenyl moieties include, but are not limited to, cyclohexenyl, cyclohexadienyl, or norbornenyl.
• heterocycloalkenyl refers to a partially saturated, nonaromatic 5- 10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively).
• the unsaturated carbon or the heteroatom may optionally be the point of attachment of the heterocycloalkenyl substituent.
• heterocycloalkenyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of heterocycloalkenyl include but are not limited to tetrahydropyridyl and
• heteroaryl refers to an alkyl group substituted with a heteroaryl group.
• oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
• acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted (e.g., by one or more substituents).
• substituted refers to a group “substituted” on a cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, cycloalkenyl, aryl, aralkyl, heteroaryl or heteroaralkyl group at any atom of that group. Any atom can be substituted.
• Suitable substituents include, without limitation, alkyl (e.g., CI, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cll, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF 3 ), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl,
• heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF 3 ), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl amino, SO 3 H, sulfate, phosphate, methylenedioxy (-O-CH 2 -O- wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C S), imino (alkyl, aryl, aralkyl), S(0) n alkyl (where n is 0-2), S(0) n aryl (where n is 0-2), S(0) n heteroaryl (where n is 0-2), S(0) n heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl,
• Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
• a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
• Fig. 1 depicts the amino acid sequence of IDH1 (SEQ ID NO: l).
• Fig. la depicts the cDNA sequence of IDH1 (SEQ ID NO:2).
• Fig. lb depicts the mRNA sequence of IDH1 (SEQ ID NO: 3).
• Fig. 2 depicts the amino acid sequence of IDH2 (SEQ ID NO:4).
• Fig. 2a depicts the cDNA sequence of IDH2 (SEQ ID NO: 5).
• Fig. 2b depicts the mRNA sequence of IDH2 (SEQ ID NO: 6).
• an IDH enzyme e.g., IDH1 or IDH2
• a neoactivity a gain of function
• the methods include, e.g., treating a subject having a glioma or brain tumor, or AML by administering to the subject a therapeutically effective amount a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I).
• IDH isocitrate dehydrogenase
• a compound and/or pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt
• W, X, Y and Z are each independently selected from CH or N;
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are independently selected from a bond, oxygen or NR C ;
• A is optionally substituted aryl or optionally substituted heteroaryl
• R 1 is independently selected from alkyl, acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 3 is independently selected from halo, haloalkyl, alkyl and -OR a ; each R a is independently selected from alkyl, and haloalkyl;
• each R c is independently selected from hydrogen, alkyl and alkenyl; each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• h 0, 1, 2;
• g 0, 1 or 2.
• a compound or pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt
• W, X, Y and Z are each independently selected from CH or N;
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are independently selected from a bond, oxygen or NR C ;
• A is aryl or heteroaryl each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from alkyl, acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , -C(0)NR c R c' , cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, or heteroaralkyl; each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and -OR a , or two R 3 s (when n is 2) taken together with the carbon atoms they are attached to form an optionally substituted heterocyclyl;
• each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl; each R b is independently alkyl;
• each R c and R c is independently selected from hydrogen, alkyl, alkyl- C(0)OR b and alkenyl;
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• h 0, 1, 2;
• g 0, 1 or 2.
• R 1 is independently selected from alkyl, -C(0)R e , - C(0)OR e , -C(0)NR c R c , cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ; wherein R e is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and heterocyclyl.
• B and B 1 are taken together with the carbon to which they are attached form a carbonyl group.
• h is 1. In some embodiments, h is 2.
• g is 1. In some embodiments, g is 2.
• both h and g are 1. In some embodiments, h is 1 and g is 2. In some embodiments, g is 1 and h is 2.
• W, X, Y and Z are CH. In some embodiments, at least one of W, X, Y and Z is N. In some embodiments, at least two of W, X, Y and Z are N. In some embodiments, at least three of W, X, Y and Z are N.
• W, X, Y, Z and the carbons to which they are attached form a pyridyl ring. In some embodiments, W, X, Y, Z and the carbon atoms to which they are attached form a pyrimidyl ring. In some embodiments, W, X, Y, Z and the carbon atoms to which they are attached form a pyridazinyl ring.
• W, X and Y are CH and Z is N.
• Q is SO 2 .
• D and D 1 are both NR C .
• one of D and D 1 is a bond and the other of D and D 1 is NR C .
• D is NR C and D is a bond.
• D is a bond and D is NR C .
• R c is alkyl (e.g., methyl or ethyl).
• R c is hydrogen (H).
• R c is alkenyl (e.g., allyl).
• one of D and D 1 is oxygen and the other of D and D 1 is NR C .
• one of D and D 1 is a bond and the other of D and D 1 is NR C .
• D is a bond and D 1 is NR C .
• D is NR C and D 1 is a bond.
• R c is alkyl (e.g., methyl or ethyl).
• R c is hydrogen.
• R c is alkenyl (e.g., allyl).
• A is optionally substituted with 1 or 2 occurrences of R 2 , wherein each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -COOH, -COOR b , or -CONR c R c' .
• A is aryl.
• A is phenyl optionally substituted with 1 or 2 occurrences of R 2 , wherein each R 2 is independently selected from halo, haloalkyl, aryl, heteroaryl, alkyl (e.g., Ci-C 4 alkyl), -OR a , -COOR b , or -CONR c R c .
• A is optionally substituted phenyl (e.g., phenyl, para-tolyl, p-ethylphenyl, ortho-n- propylphenyl, para-n-propylphenyl, para-isopropylphenyl, para-n-butylphenyl, para-t- butylphenyl, para-sec-butylphenyl, ortho-anisolyl, para-anisolyl, meta-ethoxyphenyl, para-ethoxyphenyl, para-propoxyphenyl, meta-isopropoxyphenyl, pata-butoxyphenyl, para-(cyclopropylmethoxy)phenyl, ortho-fluorophenyl, para-chlorophenyl, para- fluoro-ortho-methylphenyl, para-methylsulfonylbenzene, 2,5-dimethoxy-5- chlorophenyl, para-e
• phenyl e.
• A is phenyl substituted with 1 occurrence of R 2 .
• R 2 is alkyl (e.g., methyl, ethyl, H-propyl, isopropyl, H-butyl, i-butyl or seobutyl).
• R 2 is halo.
• R 2 is fluorine (F).
• R 2 is bromine (Br).
• R 2 is chlorine (CI).
• R 2 is alkyl-NR c R c (e.g., ethyl-NR c R c ). In a more particular aspect of these embodiments, R c and R c are alkyl (e.g., methyl). In another aspect of these embodiments, R 2 is aralkyl (e.g., benzyl or 2-phenylethyl). In some embodiments, R 2 is NR C R C . In one aspect of this embodiment, R c and R c are alkyl (e.g., methyl). In some embodiments, R 2 is -OR a .
• R a is alkyl (e.g., methyl, n- ethyl, propyl, isopropyl, H-butyl or methylcyclopropyl).
• R a is alkylalkoxy (e.g., methylmethoxy).
• R a is alkylalkoxylalkoxy (e.g., methylethyoxylmethoxy).
• R a is alkyl-C(0)OR b (e.g., methyl-C(0)OR b or ethyl- 1- C(0)OR b ).
• R b is ethyl.
• A is phenyl substituted with 2 occurrences of R 2 .
• both R 2 are halo (e.g., fluorine or chlorine).
• both R 2 are alkyl (e.g, methyl). In some embodiments, both R 2 are - OR a . In some embodiments, one R 2 is halo and the other is -OR a . In some embodiments, one R 2 is bromine (BR) and the other is -OR a . In some embodiments, one R 2 is chlorine (CI) and the other is -OR a . In some embodiments, one R 2 is fluorine (F) and the other is -OR a . In some embodiments, R a is alkyl (e.g., methyl or ethyl).
• one R 2 is alkyl (e.g., H-butyl) and the other R 2 is - COOH. In some embodiments, one R 2 is hydroxyl and one R 2 is -OR a . In some aspect of this embodiments, R a is alkyl (e.g., methyl). In some embodiments, one R 2 is alkyl (e.g., n-butyl) and one R 2 is -NR C R C . In one aspect of this embodiment, R c and R c is alkyl (e.g., methyl).
• A is phenyl substituted with 3 occurrences of R 2 .
• two R 2 are alkyl (e.g., methyl) and one is -OR a .
• R a is alkyl (e.g., H-butyl).
• R 1 is acyl. In an aspect of this embodiment, R 1 is a ketone (e.g., phenylcarbonyl or benzylcarbonyl). In another aspect of this
• R 1 is an ester (e.g., -C(0)Obenzyl, -C(0)Oisobutyl or - C(O)Oisopropyl).
• R is aryl (e.g., monocyclic or bicyclic aryl).
• R 1 is 5-8 membered monocyclic aryl (e.g., phenyl).
• R 1 is optionally substituted phenyl.
• R 1 is optionally substituted phenyl.
• each R d is independently selected from halo, haloalkyl, alkyl, aryl, -OR a wherein R a is as defined above.
• p is 0. In some embodiments, p is 1. In some embodiments, R d is ortho substituted. In some embodiments, R d is meta substituted. In some embodiments, R d is para substituted. In some embodiments, R d is halo (e.g., fluorine, chlorine or bromine). In some embodiments, R d is aryl (e.g., phenyl). In some embodiments, R d is -OR a . In some embodiments, R a is alkyl (e.g., methyl, ethyl, H-propyl, isopropyl, isobutyl, methylcyclopropyl). In another aspect of these embodiments, R a is aryl (e.g., phenyl). In another aspect of this embodiment, R a is aralkyl (e.g., benzyl or 2-phenylethyl).
• p is 2.
• the two R d are ortho and meta substituted.
• the two R d are ortho and para substituted.
• the two R d are meta and para substituted.
• both R d are alkyl (e.g., methyl).
• R 1 is heteroaryl (e.g., N-containing monocyclic heteroaryl or N-containing bicyclic heteroaryl). In some embodiments, R 1 is a 5-8 membered monocyclic heteroaryl (e.g., pyridyl, pyrimidyl or pyrizyl).
• R 1 is optionally substituted pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4- pyridyl, 4-trifluoromethyl-6-chloro-2-pyridyl or 2-methoxy-3 -pyridyl), optionally substituted pyrimidyl (e.g., 2-pyrimidyl or 5-pyrimidyl) or optionally substituted pyrizinyl (e.g., 2-pyrinzinyl).
• R 1 is optionally substituted thiazolyl (e.g., 2-thiazolyl).
• R 1 is an 8-12 membered bicyclic heteroaryl.
• R is pyrrolo[2,3-b]pyridyl (e.g., 4-pyrrolo[2,3- bjpyridyl).
• R 1 is alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is acyl (e.g., acetyl). In some embodiments, R 1 is optionally substituted pyrimidyl (e.g., 2-pyrimidyl). In some embodiments, R 1 is 4-chloro-2-pyrimidyl. In some embodiments, R 1 is optionally substituted pyrazinyl.
• R 1 is optionally substituted aralkyl (e.g., benzyl, phenylethyl, 2-phenylethyl, 2-ethylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 2,4,5- trimethylbenzyl, 2,3,4-trimethylbenzyl, 2-phenylpropyl or 3-phenylpropyl).
• R 1 is optionally substituted heteroaralkyl (e.g., methyl-pyridyl or methyl-pyrimidyl) .
• n is 0. In some embodiments, n is 1. In some embodiments, n is 1 and R 3 is positioned on W.
• R 3 is alkyl (e.g., methyl or ethyl). In some embodiments, R 3 is halo (e.g., fluorine, bromine or chlorine). In some embodiments, R 3 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 is alkenyl (e.g., vinyl). In some embodiments, R 3 is alkynyl (e.g., propynyl). In some embodiments, R 3 is heterocyclyl (e.g., morpholinyl or pyrrolidinyl).
• n is 2. In some embodiments, n is 2 and one R 3 is positioned on W and the other R 3 is positioned on Y.
• two adjacent R 3 s are taken together with the carbon atoms to which they are attached to form a heterocyclyl ring (e.g., 1,4-dioxane or morpholine).
• a heterocyclyl ring e.g., 1,4-dioxane or morpholine.
• composition comprising a compound of formula (la) or a
• R 1 , R 3 , R a , R b , R c , B, B 1 , n, h and g are as defined above.
• each of X, Y and Z are CH. In some embodiments, one of X, Y and Z are N and two of X, Y and Z are CH. In some embodiments, X is N and Y and Z are CH. In some embodiments, Y is N and X and Z are CH. In some embodiments, Z is N and X and Y are CH. In some embodiments, two of X, Y and Z are N and one of X, Y and Z are CH.
• R 1 , R 3 , R a , R b , R c , B, B 1 , n, h and g are as defined above.
• each of X, Y and Z are CH. In some embodiments, one of X, Y and Z are N and two of X, Y and Z are CH. In some embodiments, X is N and Y and Z are CH. In some embodiments, Y is N and X and Z are CH. In some embodiments, Z is N and X and Y are CH. In some embodiments, two of X, Y and Z are N and one of X, Y and Z are CH.
• W, X, Y and Z are each independently selected from CH or N;
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are independently selected from a bond or NR C ;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ; each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and -OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl;
• each R b is independently alkyl
• each R c and R c is independently selected from hydrogen, alkyl, alkyl- C(0)OR b and alkenyl;
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• h 0, 1, 2;
• g 0, 1 or 2;
• each R 3 is independently selected from halo, alkyl and -OR a ;
• h and g are each 1; one of D and D 1 is a bond and the other is NH; R 1 is phenyl or monocyclic heteroaryl, each of which may be optionally substituted with 0-3 occurrences of R d ; then A is not phenyl optionally substituted with unsubstituted alkyl, unsubstituted alkoxy, halo, CF 3 , CH 2 CH 2 NH 2 , NO 2 , or acyl;
• h and g are each 1; of D and D 1 is a bond and the other is NH; R 1 is acyl;
• n 1
• R 3 is alkyl and R 3 is connected to W, and A is not phenyl substituted by methyl, F, methoxy or ethoxy; and (iii) the sum of h and g is 3, D is a bond and D is NH; R is o- methoxyphenyl;
• A is not phenyl substituted with unsubstituted alkyl, methoxy, ethoxy or halo;
• the compound is not N-(4-butylphenyl)-N'-[3-[[4-2-(methoxyphenyl)-l- piperazinyl]carbonyl]-4-methylphenyl]-sulfamide.
• W, X, Y and Z are each independently selected from CH or N;
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and -OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl;each R c and R c' is independently selected from hydrogen, alkyl, alkyl-C(0)OR b and alkenyl;
• each R b is independently alkyl; each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• h 0, 1, 2;
• g 0, 1 or 2;
• D is a bond and D 1 is NH
• R 1 is o-methoxyphenyl
• a 1 is not phenyl substituted with unsubstituted alkyl, methoxy, ethoxy or halo;
• the compound is not N-(4-butylphenyl)-N'-[3-[[4-2-(methoxyphenyl)-l- piperazinyl]carbonyl]-4-methylphenyl]-sulf amide.
• h is 1. In some embodiments, h is 2.
• g is 1. In some embodiments, g is 2.
• both h and g are 1. In some embodiments, h is 1 and g is 2. In some embodiments, g is 1 and h is 2.
• W, X, Y and Z are each independently selected from CH or N;
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• each R 3 is independently selected from halo, haloalkyl, alkyl, alkenyl, alkynyl, heterocyclyl and -OR a , or two R 3 (when n is 2) taken together with adjacent carbon atoms form an optionally substituted heterocyclyl;
• each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl;each R c and R c' is independently selected from hydrogen, alkyl, alkyl-C(0)OR b and alkenyl;
• each R b is independently alkyl
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• the compound is not N-(4-butylphenyl)-N'-[3-[[4-2- (methoxyphenyl)-l-piperazinyl]carbonyl]-4-methylphenyl]-sulfamide.
• R 1 is independently selected from acyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d .
• R 1 is acyl.
• R 1 is a ketone (e.g., phenylcarbonyl or benzylcarbonyl).
• R 1 is an ester (e.g., -C(0)Obenzyl, -C(0)Oisobutyl or - C(O)Oisopropyl).
• R 1 is aryl (e.g., monocyclic). In one aspect of these embodiments, R 1 is 5-8 membered monocyclic aryl (e.g., phenyl). In another aspect of these embodiments, R is optionally substituted phenyl.
• R 1 is optionally substituted phenyl. In some embodiments, R 1 is represented by the following structur
• each R d is independently selected from halo, haloalkyl, alkyl, aryl, -OR a wherein R a is as defined above.
• p is 0. In another aspect of these embodiments, p is 1. In another aspect of these embodiments, R d is ortho substituted. In another aspect of these embodiments, R d is meta substituted. In another aspect of these embodiments, R d is para substituted. In another aspect of these embodiments, R d is halo (e.g., fluorine, chlorine or bromine). In another aspect of these embodiments,
• R d is aryl (e.g., phenyl). In another aspect of these embodiments, R d is -OR a . In a further aspect of these embodiments, R a is alkyl (e.g., methyl, ethyl, n- propyl, isopropyl, isobutyl, methylcyclopropyl). In another aspect of these embodiments, R a is aryl (e.g., phenyl). In another aspect of these embodiments, R a is aralkyl (e.g., benzyl or 2-phenylethyl).
• p is 2.
• the two R d are ortho and meta substituted.
• the two R d are ortho and para substituted.
• the two R d are meta and para substituted.
• both R d are alkyl (e.g., methyl).
• R 1 is heteroaryl (e.g., N- containing monocyclic heteroaryl or N-containing bicyclic heteroaryl). In some aspects of these embodiments, R 1 is a 5-8 membered monocyclic heteroaryl (e.g., pyridyl, pyrimidyl or pyrizyl).
• R 1 is optionally substituted pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-trifluoromethyl- 6-chloro-2-pyridyl or 2-methoxy-3-pyridyl), optionally substituted pyrimidyl (e.g., 2- pyrimidyl or 5-pyrimidyl) or optionally substituted pyrizinyl (e.g., 2-pyrinzinyl).
• R 1 is optionally substituted thiazolyl (e.g., 2- thiazolyl).
• R 1 is an 8-12 membered bicyclic heteroaryl.
• R 1 is pyrrolo[2,3-b]pyridyl (e.g., 4-pyrrolo[2,3-b]pyridyl).
• R 1 is optionally substituted pyrimidyl (e.g., 2-pyrimidyl).
• R 1 is 4-chloro-2-pyrimidyl.
• R 1 is optionally substituted pyrazinyl.
• R 1 is optionally substituted aralkyl (e.g., benzyl, phenylethyl, 2-phenylethyl, 2-ethylbenzyl, 2- methylbenzyl, 3-methylbenzyl, 2,4,5-trimethylbenzyl, 2,3,4-trimethylbenzyl, 2- phenylpropyl or 3-phenylpropyl).
• R 1 is optionally substituted heteroaralkyl (e.g., methyl-pyridyl or methyl-pyrimidyl).
• B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are independently selected from a bond or NR C ;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from cycloalkyl, aryl, heteroaryl or heterocyclyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• each R 3 is independently selected from halo, haloalkyl, alkyl and -OR a , or two adjacent R 3 s (when n is 2) taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl;each R c and R c' is independently selected from hydrogen, alkyl, alkyl-C(0)OR b and alkenyl;
• each R b is independently alkyl
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2;
• each R 3 is independently selected from halo, alkyl and -OR a ;
• one of D and D 1 is a bond and the other is NH;
• R 1 is phenyl or monocyclic heteroaryl, each of which may be optionally substituted with 0-3 occurrences of R d ;
• A is not phenyl optionally substituted with unsubstituted alkyl, unsubstituted alkoxy, halo, CF 3 , CH 2 CH 2 NH 2 , N0 2 , or acyl.
• R 1 is aryl .
• R 1 is 5-8 membered monocyclic aryl (e.g., phenyl).
• R 1 is optionally substituted phenyl.
• R 1 is optionally substituted phenyl.
• each R d is independently selected from halo, haloalkyl, alkyl, aryl, -OR a wherein R a is as defined above.
• p is 0. In another aspect of these embodiments, p is 1. In another aspect of these embodiments, R d is ortho substituted, In another aspect of these embodiments, R d is meta substituted. In another aspect of these embodiments, R d is para substituted. In another aspect of these embodiments, R d is halo (e.g., fluorine, chlorine or bromine). In another aspect of these embodiments, R d is aryl (e.g., phenyl). In another aspect of these embodiments, R d is -OR a .
• R a is alkyl (e.g., methyl, ethyl, n- propyl, isopropyl, isobutyl, methylcyclopropyl).
• R a is aryl (e.g., phenyl).
• R a is aralkyl (e.g., benzyl or 2-phenylethyl).
• p is 2.
• the two R d are ortho and meta substituted.
• the two R d are ortho and para substituted.
• the two R d are meta and para substituted.
• both R d are alkyl (e.g., methyl).
• R 1 is heteroaryl (e.g., N-containing monocyclic heteroaryl or N-containing bicyclic heteroaryl). In some aspects of these embodiments, R 1 is a 5-8 membered monocyclic heteroaryl (e.g., pyridyl, pyrimidyl or pyrizyl).
• R 1 is optionally substituted pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-trifluoromethyl-6-chloro-2-pyridyl or 2-methoxy-3-pyridyl), optionally substituted pyrimidyl (e.g., 2-pyrimidyl or 5- pyrimidyl) or optionally substituted pyrizinyl (e.g., 2-pyrinzinyl).
• R 1 is optionally substituted thiazolyl (e.g., 2-thiazolyl).
• R 1 is an 8-12 membered bicyclic heteroaryl.
• R 1 is pyrrolo[2,3-b]pyridyl (e.g., 4-pyrrolo[2,3- bjpyridyl).
• R 1 is optionally substituted pyrimidyl (e.g., 2-pyrimidyl).
• R 1 is 4-chloro- 2-pyrimidyl.
• R 1 is optionally substituted pyrazinyl.
• B and B are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are independently selected from a bond or NR C ;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from heterocyclylalkyl, cycloalkylalkyl, aralkyl and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• each R 3 is independently selected from halo, haloalkyl, alkyl and -OR a ;
• each R a is independently selected from alkyl, alkoxy, alkylalkoxy, alkylalkoxylalkoxy, alkyl-C(0)OR b , alkyl-C(0)OR b , and haloalkyl;each R c and R c' is independently selected from hydrogen, alkyl, alkyl-C(0)OR b and alkenyl;
• each R b is independently alkyl
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• n 0, 1, or 2.
• R 1 is optionally substituted aralkyl (e.g., benzyl, phenylethyl, 2-phenylethyl, 2-ethylbenzyl, 2-methylbenzyl, 3- methylbenzyl, 2,4,5-trimethylbenzyl, 2,3,4-trimethylbenzyl, 2-phenylpropyl or 3- phenylpropyl).
• R 1 is optionally substituted heteroaralkyl (e.g., methyl-pyridyl or methyl-pyrimidyl).
• n is 0. In some embodiments, n is 1. In some embodiments n is 1 and R 3 is positioned on W.
• R 3 is alkyl (e.g., methyl or ethyl). In some embodiments, R 3 is halo (e.g., fluorine, bromine or chlorine). In some embodiments, R 3 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 is alkenyl (e.g., vinyl). In some embodiments, R 3 is alkynyl (e.g., propynyl). In some embodiments, R 3 is heterocyclyl (e.g., morpholinyl or pyrrolidinyl).
• n is 2. In some embodiments, n is 2 and one R 3 is positioned on W and the other R 3 is positioned on Y. In one aspect of this embodiment, two adjacent R 3 s are taken together with the carbon atoms to which they are attached to form a heterocyclyl ring (e.g., 1,4-dioxane or morpholine).
• a heterocyclyl ring e.g., 1,4-dioxane or morpholine
• B and B are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;
• D and D 1 are indepedently selected from a bond or NR C ;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from acyl, optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• R 3 is halo, haloalkyl, alkyl, or -OR a ;
• each R a is independently selected from alkyl and haloalkyl;each R c and R c is independently selected from hydrogen, alkyl, and alkenyl;
• each R b is independently alkyl
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
• A is not phenyl substituted by methyl, fluorine, methoxy or ethoxy.
• B and B are taken together with the carbon to which they are attached form a carbonyl group.
• R 3 is alkyl (e.g., methyl or ethyl). In some embodiments, R 3 is halo (e.g., fluorine, bromine or chlorine). In some embodiments, R 3 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 is alkenyl (e.g., vinyl). In some embodiments, R 3 is alkynyl (e.g., propynyl). In some embodiments, R 3 is heterocyclyl (e.g., morpholinyl or pyrrolidinyl).
• R 1 is acyl.
• R 1 is a ketone (e.g., phenylcarbonyl or benzylcarbonyl).
• R 1 is an ester (e.g., -C(0)Obenzyl, -C(0)Oisobutyl or - C(O)Oisopropyl).
• D and D are indepedently selected from a bond or NR C ;
• A is aryl or heteroaryl, each substituted with 0-3 occurrences of R 2 ;
• R 1 is independently selected from heterocyclylalkyl, cycloalkylalkyl, aralkyl and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;
• each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c' , -OR a , -C(0)OH, -C(0)OR b , or - C(0)NR c R c' ;
• R 3 is alkyl
• each R a is independently selected from alkyl and haloalkyl;each R c and R c is independently selected from hydrogen, alkyl, and alkenyl;
• each R b is independently alkyl
• each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and -OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; and provided that when D is a bond and D is NH, then A is not phenyl substituted with methyl or methoxy.
• D and D 1 are both NR C .
• one of D and D 1 is a bond and the other of D and D S NR'.
• D is NR C and D 1 is a bond.
• D is a bond and D 1 is NR C .
• R c is alkyl (e.g., methyl or ethyl).
• R c is hydrogen (H).
• R c is alkenyl (e.g., allyl).
• A is optionally substituted with 1 or 2 occurrences of R 2 , wherein each R 2 is independently selected from halo, hydroxy, haloalkyl, aryl, heteroaryl, alkyl, -NR C R C , alkyl-NR c R c , -OR a , -COOH, -COOR b , or -CONR c R c' .
• A is aryl).
• A is phenyl optionally substituted with 1 or 2 occurrences of R 2 , wherein each R 2 is independently selected from halo, haloalkyl, aryl, heteroaryl, alkyl (e.g., C C 4 alkyl), -OR a , -COOR b , or -CONR c R c' .
• A is optionally substituted phenyl (e.g., phenyl, para-tolyl, p-ethylphenyl, ortho-n-propylphenyl, para-n-propylphenyl, para- isopropylphenyl, para-n-butylphenyl, para-t-butylphenyl, para-sec-butylphenyl, ortho- anisolyl, para-anisolyl, meta-ethoxyphenyl, para-ethoxyphenyl, para-propoxyphenyl, meta-isopropoxyphenyl, pata-butoxyphenyl, para-(cyclopropylmethoxy)phenyl, ortho-fluorophenyl, para-chlorophenyl, para-fluoro-ortho-methylphenyl, para- methylsulfonylbenzene, 2,5-dimethoxy-5-chlorophenyl,
• phenyl e.g
• A is phenyl substituted with 1 occurrence of R 2 .
• R 2 is alkyl (e.g., methyl, ethyl, H-propyl, isopropyl, H-butyl, i-butyl or seobutyl).
• R 2 is halo.
• R 2 is fluorine (F). In yet another aspect of these embodiments, R 2 is bromine (Br). In yet another aspect of these embodiments, R 2 is chlorine (CI). In another aspect of these embodiments, R 2 is alkyl-NR c R c (e.g., ethyl-NR c R c ). In a further aspect of these embodiments, R c and R c are alkyl (e.g., methyl). In another aspect of these embodiments, R 2 is aralkyl (e.g., benzyl or 2-phenylethyl). In some embodiments, R 2 is NR C R C .
• R c and R c are alkyl (e.g., methyl).
• R 2 is -OR a .
• R a is alkyl (e.g., methyl, n- ethyl, propyl, isopropyl, H-butyl or methylcyclopropyl).
• R a is alkylalkoxy (e.g., methylmethoxy).
• R a is alkylalkoxylalkoxy (e.g., methylethyoxylmethoxy).
• R a is alkyl- C(0)OR b (e.g., methyl-C(0)OR b or ethyl- l-C(0)OR b ). In another aspect of this embodiment, R b is ethyl.
• A is phenyl substituted with 2 occurrences of R 2 .
• both R 2 are halo (e.g., fluorine or chlorine).
• both R 2 are alkyl (e.g, methyl). In some embodiments, both R 2 are - OR a . In some embodiments, one R 2 is halo and the other is -OR a . In some embodiments, one R 2 is bromine (BR) and the other is -OR a . In some embodiments, one R 2 is chlorine (CI) and the other is -OR a . In some embodiments, one R 2 is fluorine (F) and the other is -OR a . In some embodiments, R a is alkyl (e.g., methyl or ethyl).
• one R 2 is alkyl (e.g., H-butyl) and the other R 2 is - COOH. In some embodiments, one R 2 is hydroxyl and one R 2 is -OR a . In some aspect of this embodiments, R a is alkyl (e.g., methyl). In some embodiments, one R 2 is alkyl (e.g., n-butyl) and one R 2 is -NR C R C . In one aspect of this embodiment, R c and R c is alkyl (e.g., methyl).
• A is phenyl substituted with 3 occurrences of R 2 .
• two R 2 s are alkyl (e.g., methyl) and one is -OR a .
• R a is alkyl (e.g., H-butyl).
• R 3 is alkyl (e.g., methyl or ethyl). In some embodiments, R 3 is halo (e.g., fluorine, bromine or chlorine). In some embodiments, R 3 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 is alkenyl (e.g., vinyl). In some embodiments, R 3 is alkynyl (e.g., propynyl). In some embodiments, R 3 is heterocyclyl (e.g., morpholinyl or pyrrolidinyl).
• R is optionally substituted aralkyl (e.g., benzyl, phenylethyl, 2-phenylethyl, 2-ethylbenzyl, 2-methylbenzyl, 3- methylbenzyl, 2,4,5-trimethylbenzyl, 2,3,4-trimethylbenzyl, 2-phenylpropyl or 3- phenylpropyl).
• R 1 is optionally substituted heteroaralkyl (e.g., methyl-pyridyl or methyl-pyrimidyl).
• a compound described herein may be an inhibitor of IDHlm.
• the inhibitory activity of these compounds is represented as an IC 50 (as measured in an assay similar to one described in Example 1) in the Table below and throughout the application.
• IC 50 as measured in an assay similar to one described in Example 1.
• A refers to an inhibitor of IDHlm with an IC 50 ⁇ 1 ⁇ .
• B refers to an inhibitor of IDHlm with an IC 50 between 1 ⁇ and 50 ⁇ .
• C refers to an inhibitor of IDHlm with an IC 50 greater than 50 ⁇ .
• D refers to a compound wherein an IC 50 is not available.
• Scheme 1 above is an exemplary scheme that depicts a representative synthesis of certain compounds described herein.
• Sulfonyl chloride 1 is reacted with amine 2 under standard coupling conditions to produce ester 3.
• Hydrolysis of 3 using lithium hydroxide generates carboxylic acid 4.
• Piperazine (5) is coupled with the appropriate bromide under standard palladium coupling conditions to provide 7.
• Carboxylic acid 4 is then treated with piperazine derivative 7 to produce final compound 8.
• the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention as described below.
• the compounds of this invention include the compounds themselves, as well as their salts and their prodrugs, as described below.
• the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
• the compounds of this invention may be modified by appending appropriate functionalities to enhance selected biological properties, e.g., targeting to a particular tissue.
• modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• the compounds described herein may be used as platforms or scaffolds that may be utilized in combinatorial chemistry techniques for preparation of derivatives and/or chemical libraries of compounds.
• Such derivatives and libraries of compounds have biological activity and are useful for identifying and designing compounds possessing a particular activity.
• Combinatorial techniques suitable for utilizing the compounds described herein are known in the art as exemplified by Obrecht, D.
• one embodiment relates to a method of using the compounds described herein for generating derivatives or chemical libraries comprising: 1) providing a body comprising a plurality of wells; 2) providing one or more compounds identified by methods described herein in each well; 3) providing an additional one or more chemicals in each well; 4) isolating the resulting one or more products from each well.
• An alternate embodiment relates to a method of using the compounds described herein for generating derivatives or chemical libraries comprising: 1) providing one or more compounds described herein attached to a solid support; 2) treating the one or more compounds identified by methods described herein attached to a solid support with one or more additional chemicals; 3) isolating the resulting one or more products from the solid support.
• tags or identifier or labeling moieties may be attached to and/or detached from the compounds described herein or their derivatives, to facilitate tracking, identification or isolation of the desired products or their intermediates.
• moieties are known in the art.
• the chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. Examples of such chemicals are those that appear in the various synthetic and protecting group chemistry texts and treatises referenced herein.
• Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomer, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
• a compound described herein e.g., an inhibitor of a neoactivity or 2-HG is an enantiomerically enriched isomer of a stereoisomer described herein.
• the compound has an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
• Enantiomer when used herein, refers to either of a pair of chemical compounds whose molecular structures have a mirror-image relationship to each other.
• a preparation of a compound disclosed herein is enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter, e.g., the 2-position of 2-hydroxyglutaric acid.
• 2HG can be purchased from commercial sources or can be prepared using methods known in the art, for example, as described in Org. Syn. Coll vol., 7, P-99, 1990.
• the compound has a purity corresponding to a compound having a selected stereochemistry of a selected stereocenter of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
• a composition described herein includes a preparation of a compound disclosed herein that is enriched for a structure or structures having a selected stereochemistry, e.g., R or S, at a selected stereocenter, e.g., the 2-position of 2-hydroxyglutaric acid.
• a selected stereochemistry e.g., R or S
• exemplary R/S configurations can be those provided in an example described herein.
• An "enriched preparation,” as used herein, is enriched for a selected stereoconfiguration of one, two, three or more selected stereocenters within the subject compound. Exemplary selected stereocenters and exemplary
• stereoconfigurations thereof can be selected from those provided herein, e.g., in an example described herein.
• enriched is meant at least 60%, e.g., of the molecules of compound in the preparation have a selected stereochemistry of a selected stereocenter. In an embodiment it is at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
• Enriched refers to the level of a subject molecule(s) and does not connote a process limitation unless specified.
• isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
• a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
• a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
• a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Cl-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl) .
• Cl-7alkyl includes n-propyl and iso-propyl
• butyl includes n-, iso-, sec-, and tert-butyl
• methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl
• keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
• H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 160 and 180; and the like.
• a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
• a corresponding salt of the active compound for example, a pharmaceutically- acceptable salt.
• a pharmaceutically- acceptable salt examples are discussed in Berge et al, 1977, "Pharmaceutically Acceptable Salts.” J. Pharm. ScL. Vol. 66, pp. 1-19.
• a salt may be formed with a suitable cation.
• suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al +3 .
• suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4+ ) and substituted ammonium ions (e.g., NH 3 R "1" , NH 2 R 2+ , NHR 3+ , NR 4+ ).
• substituted ammonium ions examples include those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,
• benzylamine phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
• amino acids such as lysine and arginine.
• An example of a common quaternary ammonium ion is N(C]3 ⁇ 4) 4+ .
• a salt may be formed with a suitable anion.
• suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
• Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, gluchep tonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
• a reference to a particular compound also includes salt forms thereof.
• chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
• specified conditions e.g., pH, temperature, radiation, solvent, and the like.
• well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
• one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
• a compound which has two nonequivalent reactive functional groups may be derivatized to render one of the functional groups "protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group.
• the protected group may be "deprotected" to return it to its original functionality.
• an ether -OR
• the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
• an amine group may be protected, for example, as an amide (- NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO- CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (- NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO- OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH- Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (
• a carboxylic acid group may be protected as an ester for example, as: an alkyl ester (e.g., a methyl ester; a t-butyl ester); a haloalkyl ester (e.g., a Cl-7trihaloalkyl ester); a triCl-7alkylsilyl-Cl-7alkyl ester; or a C5.2oaryl-Cl- 7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
• an alkyl ester e.g., a methyl ester; a t-butyl ester
• a haloalkyl ester e.g., a Cl-7trihaloalkyl ester
• a triCl-7alkylsilyl-Cl-7alkyl ester e.g., a benz
• -SR thioether
• benzyl thioether an acetamidomethyl ether
• a cell proliferation-related disorder e.g., a cancer, e.g., a glioma, AML, prostate cancer, thyroid cancer, fibrosarcoma or melanoma, e.g., by inhibiting a neoactivity of a mutant IDH enzyme, e.g., IDHl or IDH2.
• the cancer can be characterized by the presence of a neoactivity.
• the gain of function is the conversion of a-ketoglurarate to 2- hydroxyglutarate, e.g., R-2-hydroxyglutarate.
• the IDH-related methods disclosed herein are directed to subjects having a cell proliferation-related disorder characterized by an IDH mutant, e.g., an IDHl or IDH2, mutant having neoactivity, e.g., 2HG neoactivity.
• IDH mutant e.g., an IDHl or IDH2 mutant having neoactivity, e.g., 2HG neoactivity.
• examples of some of the disorders below have been shown to be characterized by an IDHl or IDH2 mutation.
• Others can be analyzed, e.g., by sequencing cell samples to determine the presence of a somatic mutation at amino acid 132 of IDHl or at amino acid 172 of IDH2. Without being bound by theory it is expected that a portion of the tumors of given type of cancer will have an IDH, e.g., IDHl or IDH2, mutant having 2HG neoactivity.
• the disclosed methods are useful in evaluating or treating proliferative disorders, e.g. evaluating or treating solid tumors, soft tissue tumors, and metastases thereof wherein the solid tumor, soft tissue tumor or metastases thereof is a cancer described herein.
• Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of brain, lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary.
• Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non- small cell carcinoma of the lung, and cancer of the small intestine.
• the disclosed methods are also useful in evaluating or treating non-solid cancers.
• a cancer can be evaluated to determine whether it is using a method described herein.
• Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult;
• Adrenocortical Carcinoma Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic;
• Lymphoma Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas);
• Lymphoma Non-Hodgkin' s, Adult
• Lymphoma Non- Hodgkin's, Childhood
• Lymphoma Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal
• Non-Hodgkin's Lymphoma Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive
• Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
• the methods described herein are useful in treating cancer in nervous system, e.g., brain tumor, e.g., glioma, e.g., glioblastoma multiforme (GBM), e.g., by inhibiting a neoactivity of a mutant enzyme, e.g., an enzyme in a metabolic pathway, e.g., a metabolic pathway leading to fatty acid biosynthesis, glycolysis,
• GBM glioblastoma multiforme
• glutaminolysis glutaminolysis, the pentose phosphate shunt, the nucleotide biosynthetic pathway, or the fatty acid biosynthetic pathway, e.g., IDH1 or IDH2.
• Gliomas a type of brain tumors, can be classified as grade I to grade IV on the basis of histopathological and clinical criteria established by the World Health Organization (WHO).
• WHO grade I gliomas are often considered benign.
• Gliomas of WHO grade II or III are invasive, progress to higher-grade lesions.
• WHO grade IV tumors are the most invasive form.
• Exemplary brain tumors include, e.g., astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma);
• astrocytic tumor e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult gli
• oligodendroglial tumor e.g., oligodendroglioma, and anaplastic oligodendroglioma
• oligoastrocytic tumor e.g., oligoastrocytoma, and anaplastic oligoastrocytoma
• ependymoma e.g., myxopapillary ependymoma, and anaplastic ependymoma
• medulloblastoma primitive neuroectodermal tumor, schwannoma, meningioma, meatypical meningioma, anaplastic meningioma
• Exemplary cancers are described in Acta Neuropathol (2008) 116:597-602 and N Engl J Med. 2009 Feb 19;360(8):765-73, the contents of which are each incorporated herein by reference.
• the disorder is glioblastoma.
• the disorder is prostate cancer, e.g., stage Tl (e.g., Tla, Tib and Tic), T2 (e.g., T2a, T2b and T2c), T3 (e.g., T3a and T3b) and T4, on the TNM staging system.
• the prostate cancer is grade Gl, G2, G3 or G4 (where a higher number indicates greater difference from normal tissue).
• Types of prostate cancer include, e.g., prostate adenocarcinoma, small cell carcinoma, squamous carcinoma, sarcomas, and transitional cell carcinoma. Methods and compositions of the inventin can be combined with art-known treatment.
• Art-known treatment for prostate cancer can include, e.g., active surveillance, surgery (e.g., radical prostatectomy, transurethral resection of the prostate, orchiectomy, and cryosurgegry), radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation therapy, High- Intensity Focused Ultrasound (HIFU), chemotherapy, cryosurgery, hormonal therapy (e.g.,
• antiandrogens e.g., flutamide, bicalutamide, nilutamide and cyproterone acetate, ketoconazole, aminoglutethimide), GnRH antagonists (e.g., Abarelix)), or a combination thereof.
• the compounds and compositions described herein can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, including those described herein.
• the compounds and compostions described herein also are useful for treating an aciduria subject (e.g., a 2-hydroxyglutaric aciduria subject).
• the term "treat” or “treatment” is defined as the application or administration of a compound, alone or in combination with, a second compound to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).
• a disorder e.g., a disorder as described herein
• a symptom of a disorder e.g., a disorder as described herein
• a predisposition toward a disorder e.
• an amount of a compound effective to treat a disorder refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
• an amount of a compound effective to prevent a disorder, or a "a prophylactically effective amount” of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the disorder.
• the term "subject” is intended to include human and non- human animals.
• exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject.
• non-human animals of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
• a compound or composition described herein is administered together with an additional cancer treatment.
• exemplary cancer treatments include, for example: surgery, chemotherapy, targeted therapies such as antibody therapies, immunotherapy, and hormonal therapy. Examples of each of these treatments are provided below.
• a compound or composition described herein is administered with a chemotherapy.
• Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy.
• Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes.
• Most forms of chemotherapy targe? all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
• chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, toposimerase inhibitors and others).
• antimetabolites e.g., folic acid, purine, and pyrimidine derivatives
• alkylating agents e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, toposimerase inhibitors and others.
• agents include Aclarubicin, Actinomycin, Alitretinon, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, endamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil,
• Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine,
• Vinblastine Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.
• the chemotherapy agents can be used in combination with a compound described herein, e.g., phenformin.
• Targeted therapy in some embodiments, a compound or composition described herein is administered with a targeted therapy.
• Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells.
• Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
• Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-depdendent kinase inhibitors such as Alvocidib and Seliciclib.
• Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and
• Tositumomab typically used in a variety of B-cell malignancies.
• Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab,
• the targeted therapy can be used in combination with a compound described herein, e.g., a biguanide such as metformin or phenformin, preferably phenformin.
• a biguanide such as metformin or phenformin, preferably phenformin.
• Targeted therapy can also involve small peptides as "homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
• RGDs Radionuclides which are attached to these peptides
• An example of such therapy includes BEXXAR®.
• a compound or composition described herein is administered with an immunotherapy.
• Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor.
• Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients.
• Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor' s immune cells will often attack the tumor in a graft-versus-tumor effect.
• the immunotherapy agents can be used in combination with a compound or composition described herein.
• a compound or composition described herein is administered with a hormonal therapy.
• the growth of some cancers can be inhibited by providing or blocking certain hormones.
• hormone- sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment.
• administration of hormone agonists, such as progestogens may be therapeutically beneficial.
• the hormonal therapy agents can be used in combination with a compound or a composition described herein.
• a compound or composition described herein is administered together with an additional cancer treatment ⁇ e.g., surgical removal), in treating cancer in nervous system, e.g., cancer in central nervous system, e.g., brain tumor, e.g., glioma, e.g., glioblastoma multiforme (GBM).
• an additional cancer treatment e.g., surgical removal
• cancer in nervous system e.g., cancer in central nervous system
• brain tumor e.g., glioma, e.g., glioblastoma multiforme (GBM).
• GBM glioblastoma multiforme
• Temozolomide is an orally active alkylating agent that is used for persons newly diagnosed with glioblastoma multiforme. It was approved by the United States Food and Drug Administration (FDA) in March 2005. Studies have shown that the drug was well tolerated and provided a survival benefit. Adjuvant and concomitant temozolomide with radiation was associated with significant improvements in median progression-free survival over radiation alone (6.9 vs 5 mo), overall survival (14.6 vs 12.1 mo), and the likelihood of being alive in 2 years (26% vs 10%).
• BCNU carmustine-polymer wafers
• Gliadel wafers were approved by the FDA in 2002. Though Gliadel wafers are used by some for initial treatment, they have shown only a modest increase in median survival over placebo (13.8 vs. 11.6 months) in the largest such phase III trial, and are associated with increased rates of CSF leak and increased intracranial pressure secondary to edema and mass effect.
• MGMT is a DNA repair enzyme that contributes to temozolomide resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastoma multiformes, results in an epigenetic silencing of the gene, decreasing the tumor cell's capacity for DNA repair and increasing susceptibility to temozolomide.
• temozolomide is currently a first-line agent in the treatment of glioblastoma multiforme, unfavorable MGMT methylation status could help select patients appropriate for future therapeutic investigations.
• interference-mediated silencing of MGMT offer promising avenues to increase the effectiveness of temozolomide and other alkylating antineoplastics, and such agents are under active study.
• Carmustine (BCNU) and cis -platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas. All agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%.
• BBB blood-brain barrier
• CED convection-enhanced delivery
• Chemotherapy for recurrent glioblastoma multiforme provides modest, if any, benefit, and several classes of agents are used.
• Carmustine wafers increased 6-month survival from 36% to 56% over placebo in one randomized study of 222 patients, though there was a significant association between the treatment group and serious intracranial infections.
• Genotyping of brain tumors may have applications in stratifying patients for clinical trials of various novel therapies.
• the anti- angiogenic agent bevacizumab when used with irinotecan improved 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with temozolomide.
• This bevacizumab and irinotecan combination for recurrent glioblastoma multiforme has been shown to improve survival over bevacizumab alone.
• Anti- angiogenic agents also decrease peritumoral edema, potentially reducing the necessary corticosteroid dose.
• Some glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors).
• tyrosine kinase inhibitors tyrosine kinase inhibitors.
• the simultaneous presence in glioblastoma cells of mutant EGFR (EGFRviii) and PTEN was associated with responsiveness to tyrosine kinase inhibitors, whereas increased p-akt predicts a decreased effect.
• Other targets include PDGFR, VEGFR, mTOR, farnesyltransferase, and PI3K.
• Other possible therapy modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
• compositions and routes of administration are provided.
• compositions delineated herein include the compounds delineated herein (e.g., a compound described herein), as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
• pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
• Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-oc-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
• Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ - cyclodextrin, or chemically modified derivatives such as hy droxy alky Icy clodextrins, including 2- and 3-hydroxypropyl- -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
• compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
• the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with
• parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• suitable vehicles and solvents that may be employed are mannitol, water, Ringer' s solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
• surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
• carriers which are commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
• compositions of this invention may also be administered in the form of suppositories for rectal administration.
• These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
• Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application.
• the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
• compositions of this invention may be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
• the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
• both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
• the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
• the compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally,
• the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
• the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a typical preparation will contain from about 5% to about 95% active compound (w/w).
• such preparations contain from about 20% to about 80% active compound.
• a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
• neoactivity refers to alpha hydroxy neoactivity. Neoactivity and alpha hydroxyl neoactivity are used interchanagly herein.
• Alpha hydroxy neoactivity is the ability to convert an alpha ketone to an alpha hydroxy. Neoactivity can arise as a result of a mutation, e.g., a point mutation, e.g., a substitution, e.g., in the active site of an enzyme.
• the neoactivity is substantially absent from wild type or non-mutant enzyme. This is sometimes referred to herein as a first degree neoactivity.
• first degree neoactivity is a "gain of function" wherein the mutant enzyme gains a new catalytic activity.
• the neoactivity is present in wild type or non-mutant enzyme but at a level which is less than 10, 5, 1, 0.1, 0.01 or 0.001 % of what is seen in the mutant enzyme. This is sometimes referred to herein as a second degree neoactivity.
• An example of a second degree neoactivity is a "gain of function" wherein the mutant enzyme has an increase, for example, a 5 fold increase in the rate of a catalytic activity possessed by the enzyme when lacking the mutation.
• a non-mutant form the enzyme e.g., a wild type form, converts substance A (e.g., isocitrate) to substance B (e.g., a-ketoglutarate), and the neoactivity converts substance B (e.g., a-ketoglutarate) to substance C, sometimes referred to as the neoactivity product (e.g., 2-hydroxyglutarate, e.g., R-2- hydroxy glutarate) .
• substance A e.g., isocitrate
• substance B e.g., a-ketoglutarate
• the neoactivity product e.g., 2-hydroxyglutarate, e.g., R-2- hydroxy glutarate
• Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+).
• NAD(+) the electron acceptor
• NADP(+) the NADP(+) -dependent isocitrate dehydrogenases
• Each NADP(+) -dependent isozyme is a homodimer.
• IDH1 isocitrate dehydrogenase 1 (NADP+), cytosolic
• IDP isocitrate dehydrogenase 1
• IDCD isocitrate dehydrogenase 1
• PICD PICD
• the protein encoded by this gene is the NADP(+)- dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for
• cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
• the human IDH1 gene encodes a protein of 414 amino acids.
• the nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM_005896.2 and NP_005887.2 respectively.
• the nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al, Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et al, J. Biol. Chem. 274:30527-30533(1999); Wiemann et al, Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al, Submitted (DEC-2008) to UniProtKB;
• IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial
• IDH isocitrate dehydrogenase 2 (NADP+), mitochondrial
• IDP isocitrate dehydrogenase 2
• IDHM isocitrate dehydrogenase 2
• ICD-M isocitrate dehydrogenase 2
• mNADP-IDH isocitrate dehydrogenase 2 (NADP+), mitochondrial
• the protein encoded by this gene is the NADP(+) -dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex.
• Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively.
• nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al, Submitted (NOV-1992) to the EMB L/GenB ank/DDB J databases; and The MGC Project Team, Genome Res. 14:2121-2127(2004).
• Non-mutant e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of ioscitrate to a-ketoglutarate thereby reducing NAD + (NADP + ) to NADP (NADPH), e.g., in the forward reaction:
• the neoactivity of a mutant IDH1 can have the ability to convert a-ketoglutarate to 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate:
• NADH NADPH + H + ⁇ 2-hydroxyglutarate, e.g., R-2- hydroxyglutarate + NAD + (NADP + ).
• the neoactivity can be the reduction of pyruvate or malate to the corresponding a-hydroxy compounds.
• the neoactivity of a mutant IDH1 can arise from a mutant IDH1 having a His, Ser, Cys or Lys, or any other mutations described in Yan et al., at residue 132.
• the neoactivity of a mutant IDH2 can arise from a mutant IDH2 having a Gly, Met or Lys, or any other mutations described in Yan H et al., at residue 140 or 172.
• Exemplary mutations include the following: R132H, R132C, R132S, R132G, R132L, R132V, and R140Q.
• the mutant IDH1 and/or IDH2 ⁇ e.g., a mutant IDH1 and/or IDH2 having a neoactivity described herein) could lead to an increased level of 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate in a subject.
• 2-hydroxyglutarate e.g., R-2-hydroxyglutarate
• elevated levels of 2- hydroxyglutarate can lead to and/or be predictive of cancer in a subject such as a cancer of the central nervous system, e.g., brain tumor, e.g., glioma, e.g., glioblastoma multiforme (GBM).
• a method described herein includes administering to a subject an inhibitor of the neoactivity
• 2-hydroxyglutarate can be detected, e.g., by LC/MS.
• LC/MS liquid chromatography
• Each method can be coupled by negative electrospray ionization (ESI, -3.0 kV) to triple-quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions.
• ESI, -3.0 kV negative electrospray ionization
• MRM multiple reaction monitoring
• Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo et al. J Chromatogr A 1147, 153-64, 2007).
• Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50% -95% B (buffers as defined above) over 5 minutes.
• a Synergi Hydro-RP, 100mm x 2 mm, 2.1 ⁇ particle size (Phenomonex) can be used as the column, as described above.
• Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration. Metabolite flux studies from 13 C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.
• 2HG e.g., R-2HG
• the analyte on which the determination is based is 2HG, e.g., R-2HG.
• the analyte on which the determination is based is a derivative of 2HG, e.g., R-2HG, formed in process of performing the analytic method.
• a derivative can be a derivative formed in MS analysis.
• Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., an Na adduct, e.g., as formed in MS analysis.
• an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG
• the analyte is a metabolic derivative of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, or another compound(s), e.g., a cellular compound, that is correlated to the level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R- 2HG.
• Examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, e.g., R-2HG.
• cancer cells with the neoactive mutant have elevated levels of glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.
• Exemplary 2HG derivatives include dehydrated derivatives such
• the methods described herein include evaluation of one or more parameters related to IDH, e.g., IDHl or IDH2, an alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., to evaluate the IDHl or IDH2 2HG neoactivity genotype or phenotype.
• the evaluation can be performed, e.g., to select, diagnose or prognose the subject, to select a therapeutic agent, e.g., an inhibitor, or to evaluate response to the treatment or progression of disease.
• the evaluation which can be performed before and/or after treatment has begun, is based, at least in part, on analysis of a tumor sample, cancer cell sample, or precancerous cell sample, from the subject.
• a sample from the patient can be analyzed for the presence or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, by evaluating a parameter correlated to the presence or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• An alpha hydroxy neoactivity product, e.g., 2HG, e.g., R- 2HG, in the sample can be determined by a chromatographic method, e.g., by LC-MS analysis. It can also be determined by contact with a specific binding agent, e.g., an antibody, which binds the alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, and allows detection. In an embodiment the sample is analyzed for the level of neoactivity, e.g., an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• the sample is analysed for the presence of a mutant IDH, e.g., IDHl or IDH2, protein having an alpha hydroxy neoactivity, e.g., 2HG neoactivity (or a corresponding RNA).
• a mutant protein specific reagent e.g., an antibody that specifically binds an IDH mutant protein, e.g., an antibody that specifically binds an IDH1-R132H mutant protein, can be used to detect neoactive mutant enzymeln an embodiment a nucleic acid from the sample is sequenced to determine if a selected allele or mutation of IDHl or IDH2 disclosed herein is present.
• the analysis is other than directly determining the presence of a mutant IDH, e.g., IDHl or IDH2, protein (or corresponding RNA) or sequencing of an IDH, e.g., IDHl or IDH2 gene.
• the analysis is other than directly determining, e.g., it is other than sequencing genomic DNA or cDNA, the presence of a mutation at residue 132 of IDHl and/or a mutation at residue 140 or 172 of IDH2.
• the tumor is other than a tumor of the CNS, e.g., other than a glioma, and the analysis includes determing the sequence of a mutation at position 132 of IDHl, or a mutation at position 172 of IDH2.
• the sequence of IDHl at any of position 71, or 100 or 109 can be determined, e.g., to detect the presence of a mutation having 2HG neoactivity.
• the tumor is a glioma and the presence of an IDHl 2HG neoactive mutation other than a mutation at 132 of IDHl is determined.
• the tumor is a glioma and the presence of an IDHl 2HG neoactive mutation other than a mutation at 172 at IDH2 is determined.
• the analysis can be the detection of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, or the measurement of the mutation's an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
• the sample is removed from the patient and analyzed.
• the evaluation can include one or more of performing the analysis of the sample, requesting analysis of the sample, requesting results from analysis of the sample, or receiving the results from analysis of the sample.
• analysis can include one or both of performing the underlying method or receiving data from another who has performed the underlying method.
• the evaluation which can be performed before and/or after treatment has begun, is based, at least in part, on analysis of a tissue (e.g., a tissue other than a tumor sample), or bodily fluid, or bodily product.
• tissue e.g., a tissue other than a tumor sample
• bodily fluid or bodily product.
• Exemplary tissues include lymph node, skin, hair follicles and nails.
• bodily fluids include blood, serum, plasma, urine, lymph, tears, sweat, saliva, semen, and cerebrospinal fluid.
• Exemplary bodily products include exhaled breath.
• the tissue, fluid or product can be analyzed for the presence or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, by evaluating a parameter correlated to the presence or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
• An alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, in the sample can be determined by a chromatographic method, e.g., by LC-MS analysis.
• tissue, fluid or product can be analyzed for the level of neoactivity, e.g., an alpha hydroxy neoactivity, e.g., the 2HG neoactivity.
• neoactivity e.g., an alpha hydroxy neoactivity, e.g., the 2HG neoactivity.
• the sample is analysed for the presence of a mutant IDH, e.g., IDH1 or IDH2, protein having an alpha hydroxy neoactivity, e.g., 2HG neoactivity (or a corresponding RNA).
• a mutant protein specific reagent e.g., an antibody that specifically binds an IDH mutant protein, e.g., an antibody that specifically binds an IDH1-R132H mutant protein
• a nucleic acid from the sample is sequenced to determine if a selected allele or mutation of IDH1 or IDH2 disclosed herein is present.
• the analysis is other than directly determining the presence of a mutant IDH, e.g., IDH1 or IDH2, protein (or corresponding RNA) or sequencing of an IDH, e.g., IDH1 or IDH2 gene.
• the analysis can be the detection of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, or the measurement of 2HG neoactivity.
• the tissue, fluid or product is removed from the patient and analyzed.
• the evaluation can include one or more of performing the analysis of the tissue, fluid or product, requesting analysis of the tissue, fluid or product, requesting results from analysis of the tissue, fluid or product, or receiving the results from analysis of the tissue, fluid or product.
• the evaluation which can be performed before and/or after treatment has begun, is based, at least in part, on alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, imaging of the subject.
• alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG
• magnetic resonance methods are is used to evaluate the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, in the subject.
• the subject is subjected to imaging and/or spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS e.g., analysis, and optionally an image corresponding to the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, or of the tumor, is formed.
• imaging and/or spectroscopic analysis e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS e.g., analysis
• an image corresponding to the presence, distribution, or level of an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG
• the image or a value related to the image is stored in a tangible medium and/or transmitted to a second site.
• the evaluation can include one or more of performing imaging analysis, requesting imaging analysis, requesting results from imaging analysis, or receiving the results from imaging analysis
• Described herein are methods of treating a cell proliferation-related disorder, e.g., cancer, in a subject and methods of identifying a subject for a treatment described herein. Also described herein are methods of predicting a subject who is at risk of developing cancer (e.g., a cancer associate with a mutation in an IDH enzyme (e.g., IDHl and/or IDH2)).
• the cancer is generally characterized by the presence of a neoactivity, such as a gain of function in one or more mutant IDH enzymes (e.g., IDHl or IDH2).
• the subject can be selected on the basis of the subject having a mutant gene having a neoactivity, e.g., a neoactivity described herein.
• select means selecting in whole or part on said basis.
• a subject is selected for treatment with a compound described herein based on a determination that the subject has a mutant IDH enzyme described herein.
• the mutant enzyme has a neoactivity and the patient is selected on that basis.
• the neoactivity of the enzyme can be identified, for example, by evaluating the subject or sample (e.g., tissue or bodily fluid) therefrom, for the presence or amount of a substrate, cofactor and/or product of the enzyme.
• the presence and/or amount of substrate, cofactor and/or product can correspond to the wild-type/non-mutant activity or can correspond to the neoactivity of the enzyme.
• Exemplary bodily fluid that can be used to identifty (e.g., evaluate) the neoactivity of the enzyme include amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
• blood e.g., blood plasma
• serum Cerebrospinal fluid
• cerumen cerumen
• chyme chyme
• Cowper's fluid female ejaculate
• interstitial fluid lymph
• breast milk mucus (e.g., nasal drainage or phlegm)
• mucus e.g., nasal drainage or phleg
• a subject can be evaluated for neoactivity of an enzyme using magnetic resonance.
• the mutant enzyme is IDHl and the neoactivity is conversion of a-ketoglutarate to 2-hydroxyglutarate
• the subject can be evaluated for the presence of and/or an elevated amount of 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate relative to the amount of 2-hydroxyglutarate, e.g., R-2- hydroxyglutarate present in a subject who does not have a mutation in IDHl having the above neoactivity.
• neoactivity of IDHl can be determined by the presence or elevated amount of a peak corresponding to 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate as determined by magnetic resonance.
• a subject can be evaluated for the presence and/or strength of a signal at about 2.5 ppm to determine the presence and/or amount of 2-hydroxyglutarate, e.g., R-2- hydroxyglutarate in the subject. This can be correlated to and/or predictive of a neoactivity described herein for the mutant enzyme IDH.
• the presence, strength and/or absence of a signal at about 2.5 ppm could be predictive of a response to treatment and thereby used as a noninvasive biomarker for clinical response.
• Neoactivity of a mutant IDH enzyme can also be evaluated using other techniques known to one skilled in the art.
• the presence or amount of a labeled substrate, cofactor, and/or reaction product can be measured such as a 13 C or 14 C labeled substrate, cofactor, and/or reaction product.
• the neoactivity can be evaluated by evaluating the forward reaction of the wild-type/non mutant enzyme (such as the oxidative decarboxylation of ioscitrate to a-ketoglutarate in a mutant IDHl enzyme) and/or the reaction corresponding to the neoactivity (e.g., the conversion of ⁇ -ketoglutarate to 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate in a mutant IDHl enzyme).
• the forward reaction of the wild-type/non mutant enzyme such as the oxidative decarboxylation of ioscitrate to a-ketoglutarate in a mutant IDHl enzyme
• the reaction corresponding to the neoactivity e.g., the conversion of ⁇ -ketoglutarate to 2-hydroxyglutarate, e.g., R-2-hydroxyglutarate in a mutant IDHl enzyme.
• a compound described herein can be provided in a kit.
• the kit includes (a) a compound described herein, e.g., a composition that includes a compound described herein (wherein, e.g., the compound can be an inhibitor described herein), and, optionally (b) informational material.
• the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of a compound described herein for the methods described herein.
• the kit provides materials for evaluating a subject.
• the evaluation can be, e.g., for: identifying a subject having unwanted, i.e., increased, levels (e.g., higher than present in normal or wildtype cells) of any of 2HG, 2HG neoactivity, or mutant IDHl or IDH2 protien having 2HG neoactivity (or
• RNA having a somatic mutation in IDHl or IDH2 characterized by 2HG neoactivity
• diagnosing, prognosing, or staging a subject, e.g., on the basis of having unwanted, i.e., increased, levels of 2HG, 2HG neoactivity, or mutant IDHl or IDH2 protien having 2HG neoactivity (or corresponding RNA), or having a somatic mutation in IDHl or IDH2 characterized by 2HG neoactivity
• selecting a treatment for, or evaluating the efficacy of, a treatment e.g., on the basis of the subject having unwanted, i.e., increased, levels of 2HG, 2HG neoactivity, or mutant IDHl or IDH2 protien having 2HG neoactivity (or corresponding RNA), or having a somatic mutation in IDHl or IDH2 characterized by 2HG neoactivity.
• the kit can include one or more reagent useful in the evaluation, e.g., reagents mentioned elsewhere herein.
• a detection reagent e.g., an antibody or other specific bindng reagent can be included.
• Standards or reference samples e.g., a positive or negative control standard can be included.
• the kit can include a reagent, e.g, a positive or negative control standards for an assay, e.g., a LC- MS assay.
• the kit can include a reagent, e.g., one or more of those mentioned elsewhere herein, for assaying 2HG neoactivity.
• the kit can include primers or other matierials useful for sequencing the relevant nucleic acids for identifying an IHD, e.g., IDH1 or IDH2, neoactive mutant.
• the kit can contain a reagent that provides for interrogation of the indentity, i.e., sequencing of, residue 132, 71, 100, 109, 70, 130, 133, 135, or 178 of IDH1 to determine if a neoactive mutant is present.
• the kit can include nucleic acids, e.g., an oligomer, e.g., primers, which allow sequencing of of the nucleotides that encode residue 132, 71, 100, 109, 70, 130, 133, 135, or 178 of IDH.
• the kit includes a nucleic acid whose hybridization, or ability to be amplified, is dependent on the indentity of residue 132, 71, 100, 109, 70, 130, 133, 135, or 178 of IDH.
• the kit includes a reagent, e.g., an antibody or other specific binding molecule, which can identify the presence of a neoactive mutant, e.g., a protein encoded by a neoactive mutant at 132, 71, 100, 109, 70, 130, 133, 135, or 178 of IDH.
• a kit can also include buffers, solvents, and information related to the evaluation.
• the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for administering the compound.
• the informational material can include instructions to administer a compound described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein).
• the informational material can include instructions to administer a compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.
• the informational material of the kits is not limited in its form.
• the informational material e.g., instructions
• the informational material is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet.
• the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording.
• the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein.
• the informational material can also be provided in any combination of formats.
• the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, a flavoring agent (e.g., a bitter antagonist or a sweetener), a fragrance or other cosmetic ingredient, and/or a second agent for treating a condition or disorder described herein.
• the other ingredients can be included in the kit, but in different compositions or containers than a compound described herein.
• the kit can include instructions for admixing a compound described herein and the other ingredients, or for using a compound described herein together with the other ingredients.
• a compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that a compound described herein be substantially pure and/or sterile.
• the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred.
• reconstitution generally is by the addition of a suitable solvent.
• the solvent e.g., sterile water or buffer, can optionally be provided in the kit.
• the kit can include one or more containers for the composition containing a compound described herein.
• the kit contains separate containers, dividers or compartments for the composition and informational material.
• the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet.
• the separate elements of the kit are contained within a single, undivided container.
• the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label.
• the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein.
• the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein.
• the containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.
• the kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device.
• a device suitable for administration of the composition e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device.
• the device is a medical implant device, e.g., packaged for surgical insertion.
• Assays were conducted in a volume of 76 ⁇ assay buffer (150 mM NaCl, 10 mM MgCl 2 , 20 mM Tris pH 7.5, 0.03% bovine serum albumin) as follows in a standard 384-well plate: To 25 ul of substrate mix (8 uM NADPH, 2 mM aKG), 1 ⁇ of test compound was added in DMSO. The plate was centrifuged briefly, and then 25 ⁇ of enzyme mix was added (0.2 ⁇ g/ml ICDH1 R132H) followed by a brief centrifugation and shake at 100 RPM.
• assay buffer 150 mM NaCl, 10 mM MgCl 2 , 20 mM Tris pH 7.5, 0.03% bovine serum albumin
• the reaction was incubated for 50 minutes at room temperature, then 25 ⁇ of detection mix (30 ⁇ resazurin, 36 ⁇ g/ml ) was added and the mixture further incubated for 5 minutes at room temperature.
• the conversion of resazurin to resorufin was detected by fluorescent spectroscopy at Ex544 Em590 c/o 590.
• Exemplary compounds tested in this assay include compound 1 from Table 1 which provided an IC 50 below 3 ⁇ .
• the starting material (2-bromo-l,l'-biphenyl) for Buchwald reaction was prepared from 1 ,2-dibromobenzene and phenylboronic acid in 25 % yield (Ref. - Synthesis 2009, 1137).
• the starting material (4-bromo-N,N-dimethylpyridin-2-amine) for Buchwald reaction was prepared from 4-bromopyridin-2-amine and Mel in presence of Nal in 45 % yield.
• R alkyl, aryl, cyclopropylmet yl, arylalkyl
• the product XI was prepared by following similar method used for the preparation of compound III (Scheme-1) using aryl bromide X (0.92 mmol) and tert- butyl piperazine-l-carboxylate X (0.191 g, 1.02 mmol). Crude product was purified by column chromatography (60-120 silica gel, 20% Ethyl Acetate-Hexane) to afford the pure product XI in 41-65% yields.
• the product XII was prepared by following similar method used for the preparation of compound VIII (Scheme-1) using acid VII (0.167 mmol) and amine XII (0.167 mmol). Crude mixture was purified by column chromatography (60-120 silica gel, 50% Ethyl Acetate-Hexane) to afford the pure product XIII in 45-65% yields.
• the starting material (l-bromo-2-phenoxybenzene) for Buchwald reaction was prepared from 2-bromophenol and phenylboronic acid in 45 % yield (Ref . - WO2009/66072 A2, 2009).
• the compound XIV was prepared by following similar method used for the preparation of compound VII (Scheme- 1) Sulfonyl chloride XIII (1.07 mmol) and 4- butylaniline (1.18 mmol). Crude product was purified by column chromatography (60-120 silica gel, 30% Ethyl Acetate-Hexane) to afford the pure product XIV in 45% yields.
• the sulfonamide X was prepared by following the similar method as followed for compound VI in scheme 1 using carboxylic acid VIII (0.1 gm, 0.42 mmol) and 4- chloroaniline (0.054 gm, 0.42 mmol) in (0.104 gm) 75% yield.
• the sulfonamide XII was prepared by following the similar method as followed for compound VII in scheme 1 using carboxylic acid X (0.08 gm, 0.25 mmol) and 3-(trifluoromethyl)aniline (0.040 gm, 0.25 mmol) in (0.075 gm) 65% yield.
• R1 H or OMe
• R2 H or Me
• R3 Alkyl
• N ⁇ Boc-A ⁇ -arylpiperazine (III, 0.68 mmol) was added methanolic-HCl (10 mL, 5%) which resulted in formation of a homogeneous solution and was stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum. The crude product was washed with ethyl acetate repeatedly and then dried well to afford product (IV) (90% yields) as a white solid.

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• 2010
  • 2010-12-09 JP JP2012543295A patent/JP5967827B2/ja not_active Expired - Fee Related
  • 2010-12-09 WO PCT/US2010/059778 patent/WO2011072174A1/en not_active Ceased
  • 2010-12-09 EP EP10796233.4A patent/EP2509600B1/en active Active
  • 2010-12-09 ES ES10796233.4T patent/ES2642109T3/es active Active
• 2012
  • 2012-06-08 US US13/492,159 patent/US20130035329A1/en not_active Abandoned
• 2015
  • 2015-06-03 JP JP2015113075A patent/JP2015193633A/ja not_active Withdrawn
• 2016
  • 2016-12-13 US US15/377,485 patent/US20170166541A1/en not_active Abandoned

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